Apremilast is an orally available small molecule inhibitor of phosphodiesterase (PDE4). Apremilast specifically inhibits PDE4 and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It has anti-inflammatory activity.
Apremilast, chemically termed as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide has the following structural Formula I.

EP1752148 (B1) discloses a process for the preparation of a racemic mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetamidoisoindoline-1,3-dione which comprises reacting 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl amine with 3-acetamidophthalic anhydride in acetic acid at reflux for 15 hours.
Several other approaches are also described in the literature to prepare apremilast.
U.S. Pat. No. 8,455,536 B2 (hereinafter referred to as the '536 patent) provides a process for the preparation of apremilast, wherein the process involves the steps of:
a) reducing 3-nitrophthalic acid using 10% Pd/C in a Parr hydrogenator with H2 up to 55 psi for 13 hours to obtain 3-aminopthalic acid;
b) reacting 3-aminopthalic acid with acetic anhydride at reflux temperature for 3 hours to obtain 3-acetamidophthalic anhydride;
c) resolution of racemic 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine using N-acetyl-L-leucine in methanol at reflux for 1 hour to obtain (S)-2-(3-ethoxy-4-methoxy phenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt; and
d) reacting overnight the N-acetyl-L-leucine salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine with 3-acetamidophthalic anhydride in 10 volume glacial acetic acid, at reflux temperature for 15 hours to obtain apremilast in 75% yield.
CN103864670 discloses the preparation of apremilast by condensing 1-[(R)-amino(phenyl)methyl]-2-naphthol with 3-ethoxy-4-methoxybenzaldehyde in the presence of triethyl amine in methanol to yield the naphtho[1,2-e][1,3]oxazine derivative, which upon addition of dimethylsulfone lithium salt in tetrahydrofuran gives N-[(2S)-(1-(3-ethyoxyl-4-methoxyphenyl)-2-methylsulfonylethyl)]-(1R)-(α-amino-benzyl)-2-iso naphthol which undergoes hydrogenation over Pd/C in methanol to yield 1(S)-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine, which is finally condensed with 3-acetamidophthalic anhydride in refluxing glacial acetic acid for 24 hours.
WO2012083153 A1 discloses the preparation of apremilast by acetylating (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl) isoindoline-1,3-dione (2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl)ethyl]-4-aminoisoindoline-1,3-dione) with acetic anhydride and acetic acid at 125° C. for 30 minutes.
The prior art processes disclosed above involve the use of acetic anhydride and a large quantity of solvents which are not safe for handling and are also environmental pollutants. As such, these processes are considered hazardous, complex and difficult to carry out.
Therefore, there exists a need for a more economical and efficient method of making apremilast which is suitable for industrial scale-up.